Hemoglobin contrast in magneto-motive optical doppler tomography, optical coherence tomography, and ultrasound imaging methods and apparatus

ABSTRACT

A novel contrast mechanism for imaging blood flow using magneto-motive optical Doppler tomography (MM-ODT), Optical Coherence Tomography, and Ultrasound. MM-ODT, OCT, and ultrasound combined with an externally applied temporally oscillating high-strength magnetic field detects erythrocytes moving according to the field gradient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of and claims priority to U.S.application Ser. No. 11/550,771, filed Oct. 18, 2006, hereinincorporated by reference in its entirety.

FUNDING

This invention was supported by funds from the National Institutes ofHealth (AR47551, EB002495 and EB002021) and the Texas AdvancedTechnology Program. The U.S. Government may have certain rights in theinvention.

BACKGROUND

The present invention relates in general to the art of medicaldiagnostic imaging and in particular to imaging blood flow usingmagneto-motive optical Doppler tomography (MM-ODT), Optical CoherenceTomography, or Ultrasound, which combines an externally appliedtemporally oscillating high-strength magnetic field with ODT, OCT, orUltrasound to detect erythrocytes moving according to the fieldgradient.

The accurate determination of location and flow velocity of movingparticles in highly scattering media, such as blood flow, is importantfor medical diagnostics. While the measurements of blood flow in thecoronary arteries is an important aspect in diagnosing coronary arterydiseases. Numerous non-invasive approaches have been developed usingtechniques such as Doppler ultrasound, conventional angiography, laserDoppler flowmetry and magnetic resonance angiography.

One common sensing technique involves the use of ultrasound. Using thistechnique, ultrasound is directed into the body of the patient and tinyparticles such as red blood cells, which are suspended in the bloodplasma, scatter the ultrasonic energy back towards the receiver ortransducer. The transducer then converts the back-scattered ultrasonicenergy into an electrical signal that is processed in some known mannerto determine the presence of a flow and an estimate of the flowvelocity.

Magnetic resonance imaging (MRI) is based on an imaging technique formagnetically exciting nuclear spins in a subject positioned in a staticmagnetic field by applying a radio-frequency (RF) signal of the Larmorfrequency, and reconstructing an image using MR signals induced by theexcitation. MRI is widely applied in clinical medicine because of itscapability of clearly depicting the slightest tissue of human brain invivo.

Magnetic resonance angiography (MRA) provides detailed angiographicimages of the body in a non-invasive manner. In conventional MRA, whichdoes not use contrast agents, magnetic resonance signal from flowingblood is optimized, while signal from stationary blood or tissuestructures is suppressed. In contrast-enhanced MRA, a contrast agent isinjected into the blood stream to achieve contrast between flowing bloodand stationary tissue.

The commonly known echo planar imaging (EPI) is a rapid MRI technique,which is used to produce tomographic images at high acquisition rates,typically several images per second. Functional magnetic resonanceimaging (fMRI) has been found useful in perfusion and/or diffusionstudies and in dynamic-contrast studies, etc. However, images obtainedin EPI experiments tend to be vulnerable to an artifact known as“ghosting” or “ghost images.”

Optical coherence tomography (OCT) is a technology that allows fornon-invasive, cross-sectional optical imaging of biological media withhigh spatial resolution and high sensitivity. OCT is an extension oflow-coherence or white-light interferometry, in which a low temporalcoherence light source is utilized to obtain precise localization ofreflections internal to a probed structure along an optic axis. Thistechnique is extended to enable scanning of the probe beam in thedirection perpendicular to the optic axis, building up a two-dimensionalreflectivity data set, used to create a cross-sectional gray-scale orfalse-color image of internal tissue backscatter.

OCT uses the short temporal coherence properties of broadband light toextract structural information from heterogeneous samples such asbiologic tissue. OCT has been applied to imaging of biological tissue invitro and in vivo. Systems and methods for substantially increasing theresolution of OCT and for increasing the information content of OCTimages through coherent signal processing of the OCT interferogram datahave been developed to provide cellular resolution (i.e., in the orderof 5 micrometers). During the past decade, numerous advancements in OCThave been reported including real-time imaging speeds.

In diagnostic procedures utilizing OCT, it would also be desirable tomonitor the flow of blood and/or other fluids, for example, to detectperipheral blood perfusion, to measure patency in small vessels, and toevaluate tissue necrosis. Another significant application would be inretinal perfusion analysis. Accordingly, it would be advantageous tocombine Doppler flow monitoring with the above micron-scale resolutionOCT imaging in tissue.

Conventional OCT imaging primarily utilizes a single backscatteringfeature to display intensity images. Functional OCT techniques processthe backscattered light to provide additional information onbirefringence, and flow properties. (See for example, Kemp N J, Park J,Zaatar H N, Rylander H G, Milner T E, High-sensitivity determination ofbirefringence in turbid media with enhanced polarization-sensitiveoptical coherence tomography, Journal of the Optical Society of AmericaA: Optics Image Science and Vision 2005, 22(3):552-560; Dave D P, AkkinT, Milner T E, Polarization-maintaining fiber-based opticallow-coherence reflectometer for characterization and ranging ofbirefringence, Optics Letters 2003, 28(19):1775-1777; Rylander C G, DaveD P, Akkin T, Milner T E, Diller K R, Welch M, Quantitativephase-contrast imaging of cells with phase-sensitive optical coherencemicroscopy, Optics Letters 2004, 29(13):1509-1511; de Boer J F, Milner TE, Ducros M G, Srinivas S M, Nelson J S, Polarization-sensitive opticalcoherence tomography, Handbook of Optical Coherence Tomography, NewYork: Marcel Dekker, Inc., 2002, pp 237-274.)

Since the ability to characterize fluid flow velocity using OCT wasdemonstrated by Wang et al., several phase resolved, real-time opticalDoppler tomography (ODT) approaches have been reported. (See forexample, Chen Z P, Milner T E, Dave D, Nelson J S, Optical Dopplertomographic imaging of fluid flow velocity in highly scattering media,Optics Letters 1997, 22(1):64-66; Wang X J, Milner T E, Nelson J S.

Optical Doppler tomography (ODT) combines Doppler velocimetry withoptical coherence tomography (OCT) for noninvasive location andmeasurement of particle flow velocity in highly scattering media withmicrometer-scale spatial resolution. The principle employed in ODT isvery similar to that used in radar, sonar and medical ultrasound. ODTuses a low coherence or broadband light source and opticalinterferometer to obtain high spatial resolution gating with a highspeed scanning device such as a conventional rapid scanning opticaldelay line (RSOD) to perform fast ranging of microstructure and particlemotion detection in biological tissues or other turbid media.

To detect the Doppler frequency shift signal induced by the movingparticles, several algorithms and hardware schemes have been developedfor ODT. The most straightforward method to determine the frequencyshift involves the use of a short time fast Fourier transform (STFFT).However, the sensitivity of this method is mainly dependent on the FFTtime window, which limits axial scanning speed and spatial resolutionwhen measuring slowly moving blood flow in small vessels that requireshigh velocity sensitivity. However, a phase-resolved technique candecouple the Doppler sensitivity and spatial resolution whilemaintaining high axial scanning speed.

In ODT, the Doppler frequency shift is proportional to the cosine of theangle between the probe beam and the scatterer's flow direction. Whenthe two directions are perpendicular, the Doppler shift is zero. Becausea priori knowledge of the Doppler angle is not available, andconventional intensity OCT imaging provides a low contrast image ofmicrovasculature structure, detecting small vessels with slow flow ratesis difficult. However, the Doppler angle can be estimated by combiningDoppler shift and Doppler bandwidth measurements. (See for example, PiaoD Q, Zhu Q, Quantifying Doppler Angle and Mapping Flow Velocity by aCombination of Doppler-shift and Doppler-bandwidth Measurements inOptical Doppler Tomography, Applied Optics, 2003, 42(25): 5158-5166, andU.S. Pat. No. 5,991,697 describe a method and apparatus for OpticalDoppler Tomographic imaging of a fluid flow in a highly scatteringmedium comprising the steps of scanning a fluid flow sample with anoptical source of at least partially coherent radiation through aninterferometer, which is incorporated herein by reference).

The ability to locate precisely the microvasculature is important fordiagnostics and treatments requiring characterization of blood flow.Recently, several efforts to increase blood flow contrast mechanismshave been reported including protein microspheres incorporatingnanoparticles into their shells, plasmon-resonant gold nanoshells, anduse of magnetically susceptible micrometer sized particles with anexternally applied magnetic field. (See for example, Lee T M, OldenburgA L, Sitafalwalla S, Marks D L, Luo W, Toublan F J J, Suslick K S,Boppart S A, Engineered microsphere contrast agents for opticalcoherence tomography, Optics Letters, 2003, 28(17): 1546-1548; Loo C,Lin A, Hirsch L, Lee M H, Barton J, Halas N, West J, Drezek R.Nanoshell-enabled photonics-based imaging and therapy of cancer.Technology in Cancer Research & Treatment, 2004; 3(1): 33-40; andOldenburg A L, Gunther J R, Boppart S A, Imaging magnetically labeledcells with magnetomotive optical coherence tomography, Optics Letters,2005, 30(7): 747-749.) Wang, et al., “Characterization of Fluid FlowVelocity by Optical Doppler Tomography,” Optics Letters, Vol. 20, No.11, Jun. 1, 1995, describes an Optical Doppler Tomography system andmethod which uses optical low coherence reflectrometry in combinationwith the Doppler effect to measure axial profiles of fluid flow velocityin a sample. A disadvantage of the Wang system is that it does notprovide a method to determine direction of flow within the sample andalso does not provide a method for generating a two-dimensional colorimage of the sample indicating the flow velocity and directions withinthe image.

The use of an externally applied field to move magnetically susceptibleparticles in tissue has been termed magneto-motive OCT (MM-OCT).Functional magnetic resonance imaging (fMRI) detects deoxyhemoglobinwhich is a paramagnetic molecule. However, the paramagneticsusceptibility of human tissue is very low compared to otherbiocompatible agents such as ferumoxides (nanometer sized iron oxideparticles). Therefore, it was believed that, other than differentiatingrelaxation times (T2) between oxygenated and deoxygenated blood, themagnetic field strength required to produce a retarding force on bloodflow was well above that of current imaging fields. (See also, forexample, Schenck J F., Physical interactions of static magnetic fieldswith living tissues, Progress in Biophysics and Molecular Biology 2005,87(2-3):185-204; and Taylor D S, Coryell, C. D., Magnetic susceptibilityof iron in hemoglobin. J. Am. Chem. Soc. 1938, 60:1177-1181.)

The embodiments disclosed herein are a novel extension of MM-OCT toimage hemoglobin in blood erythrocytes. In one aspect of theembodiments, the approach requires no exogenous contrast agent to detectblood flow and location.

SUMMARY OF THE INVENTION

The method and apparatus of imaging a blood flow using Doppler opticalcoherence tomography comprises an externally applied temporallyoscillating high-strength magnetic field with a Doppler opticaltomography system to detect hemoglobin moving according to the magneticfield gradient.

In another embodiment, the method and apparatus comprises a solenoidcone-shaped ferrite core with an extensively increased magnetic fieldstrength at the tip of the core. In a further embodiment, the method andapparatus comprises focusing the magnetic force on targeted samples.

Another embodiment is an apparatus for imaging blood flow, comprising:(1) a magnetomotive optical Doppler tomography (MM-ODT) imaging system;(2) an oscillating magnetic field applied to the moving blood flow; (3)a light source (4) a rapid scanning optical delay line in a referencearm and aligned such that no phase modulation is generated when thegroup phase delay is scanned at 4 kHz; and (5) a hardware in-phase and aquadrature demodulator with high bandpass filters.

Another embodiment, a method for imaging a blood flow comprises applyinga magnetic field to the blood flow, wherein the blood flow comprising aplurality of hemoglobin molecules and wherein the magnetic fieldinteracts with the hemoglobin molecules to cause a change in the bloodflow; and detecting the blood flow by detecting the change in the bloodflow caused by the interaction with the hemoglobin molecules, whereinthe change is detected using a magnetomotive optical Doppler tomographyimaging system.

Another embodiment of the method for imaging a blood flow comprisestemporally oscillating the magnetic field.

Another embodiment, an apparatus for imaging a blood flow comprises amagnetic field generator for applying a magnetic field to the bloodflow, wherein the blood flow comprises hemoglobin molecules; and anultrasound detection system for detecting the blood flow while it is inthe presence of the magnetic field.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of the MM-ODT system.

FIG. 2 is a schematic diagram of the probe beam, flow sample andsolenoid coil.

FIGS. 3 a and 3 b are OCT and ODT images of a stationary turbid solutionwithout an external magnetic field, respectively. FIG. 3 c and FIG. 3 dare OCT and ODT images with a 50 Hz magnetic field, respectively. Thewhite bar represents 200 μm, accordingly.

FIGS. 4 a-4 d are M-mode ODT images of the diluted deoxygenated bloodflow (18% hematocrit) without and with an external magnetic field. FIG.4 a and FIG. 4 b are ODT images of 5 mm/s blood flow without and with a5 Hz magnetic field, respectively. FIG. 4 c and FIG. 4 d are ODT imagesof 30 mm/s blood flow without and with a 50 Hz magnetic field,respectively. The Black bar indicates 200 μm, accordingly.

FIG. 5 a and FIG. 5 b are the Doppler frequency shift profiles withoutan external magnetic field, and with a 50 Hz magnetic field,respectively.

FIG. 6 is a block diagram illustrating an exemplary phase sensitive OCTsystem.

FIG. 7 is a graph of the optical path length change in the DP-OCTsystem.

FIG. 8 is a schematic diagram of Magneto Motive Ultrasound for Blood.

FIG. 9 is an ultrasound image of blood exposed to an oscillatingmagnetic field.

FIG. 10 is a schematic diagram of Ultrasonography and OCT coupled withmagnetic field generator.

DETAILED DESCRIPTION OF THE INVENTION

Magneto-Motive Optical Doppler Tomography (MM-ODT) for improved Dopplerimaging of blood flow using an external oscillating magnetic field isdescribed below. By introducing mechanical movement of red blood cells(RBC's) during blood flow by a temporally oscillating high-strengthmagnetic field, MM-ODT allows imaging of blood flow and velocity. Thecontrolled and increased Doppler frequency in MM-ODT provides aninvestigational tool to study in vivo blood transport, as shown in thearticle Hemoglobin Contrast in Magnetomotive Optical Doppler Tomography,Opt. Lett. 31, 778-780 (2006), herein incorporated by reference.

The microstructure of the blood flow and flow velocity information areall encoded in the interferogram of a Doppler OCT system. It should bereadily apparent to those skilled in the optical arts, that differentOCT systems and different OCT information can be used to determine theDoppler frequency shift. It is not intended to suggest any limitation asto the scope or functionality with different OCT architectures oroptical information used with an oscillating magnetic field, such astime domain Doppler OCT and spectral domain Doppler OCT. Time domain OCTrequires a mirror in the reference arm scanning at a constant velocity,while spectral domain OCT includes swept source OCT and Fourier domainOCT. An example of time-domain Doppler OCT is provided below.

A schematic of the MM-ODT apparatus 10 is shown in FIG. 1. The OCT lightsource 12 comprises a super luminescent diode, which is used as the lowcoherence light source. In one embodiment, light source 12 is centeredat 1.3 μm with a bandwidth of 90 nm. Light from source 12 is coupledinto a single-mode optical fiber based interferometer 20 by circulator14, where the interferometer 20 can provide 1 mW of optical power at thesample 60. Light is split into a reference arm 22 and sample arm 24 by a2×2 splitter 16. A rapid-scanning optical delay (RSOD) line 26 iscoupled to the reference arm 22. In one embodiment, the rapid-scanningoptical delay line 26 is aligned such that no phase modulation isgenerated when the group phase delay is scanned at ˜4 kHz. In the samplearm 24, a collimated beam 36 is redirected to sample 60 by twogalvanometers 30 that permit three-dimensional scanning. In oneembodiment, the galvanometers can be an X-scanner and a Y-scanner. Thesample 60 can be internal or external to the body, where the probe beamis focused by an objective lens 32. In one embodiment, the objectivelens 32 yields a 10-μm spot at the focal point. Phase modulation can begenerated using an electro-optical waveguide phase modulator, which canproduce a carrier frequency (˜1 MHz). And the magnetic field generator100 is in proximity to the sample 60.

A dual-balanced photodetector 34 is coupled to the 2×2 splitter 16 andthe circulator 14. The photodetector 34 of a 80 MHz bandwidth reducesthe light source noise from the OCT interference signal. A hardwarein-phase and quadrature demodulator 40 with high/bandpass filters 42 andlow/bandpass filters 44 improves imaging speed. Doppler information wascalculated with the Kasai autocorrelation velocity estimator. Labviewsoftware 50 (National Instruments, Austin, Tex.) is coupled to theMM-ODT system with a dual processor based multitasking scheme. Themaximum frame rate of the MM-ODT system 10 was 16 frames per second fora 400×512 pixel sized image. The Doppler frequency shift can bedetermined with the use of a short time fast Fourier transform (STFFT).Alternatively, a phase-resolved technique can determine the Dopplerfrequency shift to decouple the Doppler sensitivity and spatialresolution while maintaining high axial scanning speed. Alternatively,differential phase optical coherence tomography (OCT) or spectral domainphase-sensitive OCT can be used to determine the Doppler frequencyshift, as readily determined by one skilled in the optical arts.

FIG. 2 shows an example of the magnetic field generator 80 with acapillary tube 90. The magnetic field generator 80 includes a solenoidcoil 82 (Ledex 4EF) with a cone-shaped ferrite core 84 at the center anddriven by a current amplifier 86 supplying up to 960 W of power. Themagnetic field generator 80 can be placed underneath the sample 60during MM-ODT imaging. The combination of the ferrite core 84 andsolenoid coil 82 using a high power operation dramatically increases themagnetic field strength (B_(max)0.14 Tesla) at the tip of the core 82and also focuses the magnetic force on the targeted samples 60. Thesinusoidal current can vary the magnetic force applied to the capillarytube 90 in order to introduce movement of magnetic fluids, which includered blood cells that contain hemoglobin. In one embodiment, the probebeam is oriented parallel to the gradient of the magnetic field'sstrength.

The material parameter characterizing magnetic materials, includingbiological tissue, is the magnetic volume susceptibility, χ. Magneticvolume susceptibility is dimensionless in SI units and is defined by theequation M=χH, where M is the magnetization at the point in question andH is the local density of the magnetic field strength. Hemoglobin's highiron content, due to four Fe atoms in each hemoglobin molecule, and thelarge concentration of hemoglobin in human red blood cells giveHemoglobin magneto-motive effects in biological tissue. The magneticvolume susceptibility of the hemoglobin molecule consists of aparamagnetic component due to the electron spins of the four iron atoms.The paramagnetic susceptibility is given by the Curie Law,

$\begin{matrix}{\chi = \frac{\mu_{o}{N_{p}\left( {\mu_{eff}^{2}\mu_{B}^{2}} \right)}}{3{kT}}} & (1)\end{matrix}$where μ_(o) is permeability of free space and has the value 4π×10⁷ H/m,N_(p) is the volume density of paramagnetic iron atoms in hemoglobin,N_(p=)4.97×10²⁵ iron atoms/m³, μ_(eff) is the effective number of Bohrmagnetons per atom reported as 5.35, and the Bohr magneton,μ_(B)=9.274×10⁻²⁴ J/T, and Boltzmann's constant, k=1.38×10⁻²³ J/K, and Tis the absolute temperature (K). The calculated susceptibility of a RBCis about 11×10⁻⁶ assuming a 90% concentration of hemoglobin per RBC. Thecalculated susceptibility of a RBC is dependent on the oxygenation ofthe hemoglobin. The calculations can be adjusted accordingly, dependingon the oxygenation of the RBC, which can be measured by knowntechniques.

A RBC placed in a magnetic field gradient experiences forces and torquesthat tend to position and align it with respect to the field'sdirection. The magnetic force, in the direction of the probing light z,is given by

$\begin{matrix}{{F_{z} = {{m_{RBC}\frac{\delta^{2}{z(t)}}{{dt}^{2}}} = {\frac{\delta\; U}{\delta z} = {\frac{\chi\; V}{\mu_{o}}B\;\frac{\delta\; B}{\delta\; z}}}}},} & (2)\end{matrix}$

where V is the particle volume, B is the magnitude of the magnetic fluxdensity, and ΔΩ is the difference between the susceptibility of theparticle and the surrounding medium. The displacement [z(t)] of an RBCdriven by a time varying magnetic flux density can be included in theanalytic OCT fringe expression, I_(f),

$\begin{matrix}{{I_{f}a\; 2\sqrt{I_{r}I_{s}{\exp\left\lbrack {{\mathbb{i}}\left( {{2\pi\; f_{o}t} + {\frac{4\pi\;{z(t)}}{\lambda_{o}}{z(t)}}} \right)} \right\rbrack}}},} & (3)\end{matrix}$where I_(R) and I_(S) are the back scattered intensities from thereference and sample arms, respectively, f_(o) is the fringe carrierfrequency, λ_(o) is the center wavelength of the light source, and z(t)is the RBC displacement. Integration of all forces (magnetic, elastic,and viscous) on the RBC gives displacement, z(t)=A cos(4πf_(m)t) where Ais a constant in units of length and f_(m) is the modulation frequencyof the magnetic flux density. In free space, the displacement, z(t), isdominated a constant acceleration which can be, however, ignored inconfined models (i.e. blood vessel or capillary tube) with assumptionsthat, first, the probing area is much smaller than magnetic field area,and that secondly probing time starts after steady states of innerpressures. Expansion of the right-hand side of Eq. (3) using Besselfunctions gives

$\begin{matrix}{I_{f}\alpha\; 2\sqrt{I_{R}I_{S}}\left( {{\sum\limits_{k = 0}^{\infty}\left( {{J_{k}(m)}{\exp\left( {{\mathbb{i}}\; k\; 4\pi\; f_{m}t} \right)}} \right)} + {\sum\limits_{k = 0}^{\infty}\left( {\left( {- 1} \right)^{k}{J_{k}(m)}{\exp\left( {{- {\mathbb{i}}}\; k\; 4{pf}_{m}t} \right)}} \right)}} \right){\exp\left( {{\mathbb{i}}\; 2\;{\pi f}_{o}t} \right.}} & (4)\end{matrix}$

where J_(k)(m) is the Bessel function of the first kind of order k forargument m which is 4πA/λ_(o). The amplitude of the k^(th) sideband isproportional to J_(k)(m) In coherent detection, the fraction of opticalpower transferred into each of the first order sidebands is (J_(l)(m))²,and the fraction of optical power that remains in the carrier is(J_(o)(m))².

Example 1 MM-ODT Imaging of the Doppler Shift of Hemoglobin by Applyingan Oscillating Magnetic Field to a Moving Blood Sample

M-mode OCT/ODT images of a capillary glass tube filled with a stationaryturbid solution with and without an external magnetic field as a controlsample were recorded, as shown in FIGS. 3-4. A 750 μm-inner diameterglass capillary tube 200 was placed perpendicularly to the probing beam70, as shown in FIG. 2. Fluids used for flow studies were injectedthrough the tube at a constant flow rate controlled by a dual-syringepump (Harvard Apparatus 11 Plus, Holliston, Mass.) with ±0.5% flow rateaccuracy. The turbid solution was a mixture of deionized water and0.5-gm latex microspheres (μ_(s)5 mm⁻¹). The magnetic flux density andits frequency were approximately 0.14 T and 50 Hz, respectively. M-modeOCT/ODT images were acquired for 100 ms per frame. FIGS. 3 a and 3 bshow M-mode OCT and ODT images without any external magnetic field,respectively. The ODT image in FIG. 3 b contains small random phasefluctuations due to ambient vibration through the optical path. FIGS. 3c and 3 d show M-mode OCT and ODT images with a 50 Hz external magneticfield, respectively. No distinguishable Doppler shift could be observedin the ODT image FIG. 3 d indicating no interaction between the externalmagnetic field and the moving microspheres.

Deoxygenated blood was extracted from the vein of a human male's leftarm, and diluted with saline. During preparation, blood was not exposeddirectly to air so as to remain deoxygenated. To simulate flow, bloodwas injected through the capillary tube 200 by a syringe pump at arelatively constant flow rate. As FIG. 4 shows, the oscillating Dopplerfrequency shift, resulting from RBC movement, could be observed at twodifferent flow rates (5 and 30 mm/s). Because the flow direction wasnearly perpendicular to the probing beam no significant Dopplerfrequency shift was distinguishable at the 5 mm/s flow rate FIG. 4 awithout any external magnetic field. In the case of the high blood flowrate of 30 mm/s, as shown at FIG. 4 c, the Doppler frequency shiftcaused by the blood flow could be observed. And for maximum contrastenhancement, the probe beam can be directed parallel to the gradient ofthe magnetic field's strength. However, application of a 50 Hz magneticfield increased the Doppler contrast of blood at both the slow and fastflow rates as shown at FIGS. 4 b and 4 d. The high flow rate of 30 mm/sgives a higher contrast image than the low flow rate image, but theDoppler frequency shift of the former as a function of depth is lesshomogeneous than the latter, which is indicative of perturbation byblood flow. The same blood was diluted to 5 hematocrit (HCT), but no RBCmovement could be observed below 8% HCT.

Doppler frequency shift profiles were calculated from the ODT images byaveraging 20 lines at a selected depth indicated by horizontal arrows,as shown in FIGS. 4 a and 4 b. FIG. 5 a indicates no significant Dopplerfrequency shift over a 100 ms time period, whereas FIG. 5 b displays±200 to 300 Hz Doppler frequency shifts oscillating 20 times over 100 ms(200 Hz).

The Doppler frequency shift indicates that RBC's physically move intoand away from the incident light while passing through the externalmagnetic field depending on whether their magnetic properties areparamagnetic or diamagnetic, as shown in FIG. 4, and that the 200 Hzoscillation of the Doppler frequency shift correlates with the 50 Hzmagnetic field, as shown in FIG. 5. Frequencies 4 times higher than thatof the external magnetic field (f_(m)) can be observed. According to Eq.2, the frequency of the force on paramagnetic targets was twice that ofthe magnetic flux density; therefore, a 50 Hz B field displaces thetargets at 100 Hz. Although the fringe signal (Eq. 4) contains harmonicsat frequency (2f_(m)), the modulation frequency, f_(m), was set so thatthe second-order sideband (4f_(m)) was dominant as shown in FIG. 5 b.The particle motion can not be described as a pure sinusoidal functioneven if the modulated magnetic field is sinusoidal, due to the numerousforces that contribute to the motion within the field such as gravity,concentration gradient, and colloidal dispersion.

The method and apparatus is a new investigational tool to study in vivoblood transport and the first implementation of MM-ODT for improvedDoppler imaging of blood flow using an external oscillating magneticfield introducing a mechanical movement of RBC's during blood flow by atemporally oscillating high-strength magnetic field. MM-ODT to allowimaging of tissue function in a manner similar to functional magneticresonance images (f-MRI) of deoxygenated blood in organs, when thesample arm of the MM-ODT system is coupled to a probe (not shown). Suchprobes are generally known in the arts, such as endoscopic probes,catheter probes, and the like.

Alternatively, the MM-ODT can be used for Port-Wine vessel mapping andSkin Cancer vessel mapping. The MM-ODT can be used to detect bloodvessel location and size for cancer and port-wine stains, since theseconditions are characterized by blood vessel growth and increases inhemoglobin content. Accordingly, other blood vessel detection for tissueabnormality identification can be envisioned with the embodimentsdisclosed herein. Generally, the MM-ODT can be used wherever blood flowdetection is necessary in operations, chemotherapy, hemodialysis, andthe like.

A spectral domain phase sensitive OCT system 100 can be used to imagethe blood flow and determine velocity information, when an oscillatingmagnetic field is applied to the blood flow, as shown in FIG. 6.Spectral domain phase sensitive OCT generally uses a broadband lightsource in a general interferometric setup, where the mirror in thereference typically does not move or does not require a rapid scanningdelay line. A spectral interferogram is detected, in which each A-scanis entirely encoded. A Fourier transformation of the A-scan and velocitydistribution of the blood flow can be extracted by known methods. Inspectral domain Doppler OCT, the blood flow profile is the envelope of acalculated A-scan through Fourier transformation on the spectralinterferogram. Velocity information is encoded in the phase of theinterferogram. The Doppler velocity can be extracted by measuring thephase shift between two successive calculated A-scans in spectral domainDoppler OCT.

This OCT system 100 is only an example of one OCT imaging modality whichcan be used to image blood flow with a temporally oscillating magneticfield, and is not intended to suggest any limitation on the scope of OCTarchitectures applicable to the embodiments disclosed herein. Generally,the OCT system 100 includes a general-purpose computing device in theform of a computer 101 and includes a magnet control 114 and a magnet116.

Light energy is generated by a light source 117. The light source 117can be a broadband laser light source coupled into optical fiberemitting light energy over a broad range of optical frequencies. Thewavelength range can be from about 400 nanometers to about 1400nanometers. Longer wavelengths (>600 nm) can be used for deeper scanningPreferably, the light source emits light having a wavelength near theinfrared spectrum to identify hemoglobin for OCT imaging, which placeshemoglobin in motion and increases optical scattering of the hemoglobin.The light energy can be emitted over a multiplicity of opticalwavelengths, frequencies, and pulse durations to achieve OCT imaging. Asused herein, optical fiber can refer to glass or plastic wire or fiber.Optical fiber is indicated on FIG. 6 as lines connecting the variousblocks of the figures. Where light energy is described as “passing,”“traveling,” “returning,” “directed,” or similar movement, such movementcan be via optical fiber.

A fraction of the generated light energy passes from the light source117 into an optical spectrum analyzer 118. The optical spectrum analyzer118 measures optical frequency as the light energy is emitted from thelight source 117 as a function of time. The optical spectrum analyzer118 samples a portion of the light emitted by the light source 117. Theoptical spectrum analyzer 118 monitors the power spectral density oflight entering the splitter 119. The remaining fraction of light energyfrom the light source 117 passes into a splitter 119. The splitter 119can be a device with four ports, with Port 1 allowing light energy toenter the splitter 119. Ports 2 and 3 allow light energy to leave andre-enter the splitter 119 to the reference reflector 120 and OCT probe122, respectively. Port 4 allows light energy to leave the splitter 119to coupling lens 124. The splitter 119 couples the light into Port 1.The splitter 119 divides the light according to a pre-determined splitratio selected by a user. For example, the split ratio can be 50/50wherein half of the light energy entering the splitter 119 at Port 1exits the splitter 119 through Port 2 and half exits the splitter 119through Port 3. In another example, the split ratio can be 60/40 wherein60% of the light energy passes through Port 2 and 40% of the lightenergy passes through Port 3.

A fraction of the light energy (determined by the split ratio) thatexits the splitter 119 through Port 2 travels to a reference reflectorsurface 120. The light energy is reflected from the reference reflectorsurface 120 back to the splitter 119 into Port 2. The referencereflector 120 can be a planar metallic mirror or a multilayer dielectricreflector with a specified spectral amplitude/phase reflectivity. Theremaining fraction of light that entered splitter 119 through Port 1exits splitter 119 through Port 3 and enters an OCT probe 122. The OCTprobe 122 can be a turbine-type catheter as described in PatentCooperation Treaty application PCT/US04/12773 filed Apr. 23, 2004 whichclaims priority to U.S. provisional application 60/466,215 filed Apr.28, 2003, each herein incorporated by reference for the methods,apparatuses and systems taught therein. The OCT probe 122 can be locatedwithin a subject 121 to allow light reflection off of subject's 121blood flow.

The light energy that entered OCT probe 122 is reflected off of theblood flow of subject 121 once an oscillating magnetic field has beentemporally applied by magnet 116. The reflected light energy passes backthrough the OCT probe 122 into the splitter 119 via Port 3. Thereflected light energy that is returned into Port 2 and Port 3 of thesplitter 119 recombines and interferes according to a split ratio. Thelight recombines either constructively or destructively, depending onthe difference of pathlengths. A series of constructive and destructivecombinations of reflected light create an interferogram (a plot ofdetector response as a function of optical path length difference). Eachreflecting layer from the subject 121 and the blood flow will generatean interferogram. The splitter 119 can recombine light energy that isreturned through Port 2 and Port 3 so that the light energies interfere.The light energy is recombined in the reverse of the split ratio. Forexample, if a 60/40 split ratio, only 40% of the light energy returnedthrough Port 2 and 60% of the light energy returned through Port 3 wouldbe recombined. The recombined reflected light energy is directed outPort 4 of the splitter 119 into a coupling lens 137. The coupling lens137 receives light from the output of the splitter 119 and sets the beametendue (beam diameter and divergence) to match that of the opticalspectrometer 138. The coupling lens 137 couples the light into anoptical spectrometer 138. The optical spectrometer 138 can divide therecombined reflected light energy light into different opticalfrequencies and direct them to different points in space which aredetected by a line scan camera 139. The line scan camera 139 performslight to electrical transduction resulting in digital light signal data108. The digital light signal data 108 is transferred into the computer101 via the OCT input interface 111. Interface between the line scancamera 139 and computer 101 can be a Universal Serial Bus (USB), or thelike. The digital light signal data 108 can be stored in the massstorage device 104 or system memory 112 and utilized by the imageconstruction software 106 and the Labview image construction software107.

The image construction software 106 can generate an image of the bloodflow of subject 121 from the light signal data 108, by receiving lightsignal data 108 generating amplitude and phase data. The amplitude andphase data (optical path length difference (cT) or optical time-delay(T)) can be separated into discrete channels and a plot of intensity vs.depth (or amplitude vs. depth) can be generated for each channel. Suchplot is known as an A-scan, where the composition of all the A-scans cancomprise one image. And movement image construction software 107generates an image of the movement of the hemoglobin from the lightsignal data 108. The movement image construction software 107 receiveslight signal data 108 for at least two successive sweeps of the lightsource 117 or the light source performs a Fourier transform on the lightsignal data 108 generating amplitude and phase data.

Optionally, additional information can be extracted from the lightsignal data to generate additional images. The light signal data can befurther processed to generate a Stokes parameter polarimetric image whenused in conjunction with polarization detectors and polarizing lenses toextract polarization data from the light signal 108, as readily known toone skilled in the art of optical coherence tomography. The differentialphase OCT image data is shown in FIG. 7, indicating the optical pathdifference with the magnetic field. Filters can be added to reduce thenoise of the signal generated by the magnetic field.

Alternatively, the phase sensitive OCT system 100 can be configured forswept source OCT, which is a different type of spectral domain OCT. Inswept source OCT, a tunable laser source replaces the broadband laserlight source 117. The scanning rate can be at wavelengths of 800 nm-1500nm. Also, the reference reflector surface 120 is in-line with samplepath 120. The optical spectrometer 125 and line scan camera 126 arereplaced with a general photodetector.

In another embodiment, an enhanced detection of cancer with ultrasoundimaging 200 is provided. Ultrasonography is the ultrasound-baseddiagnostic imaging technique used to visualize muscles and internalorgans, their size, structures and any pathological lesions.“Ultrasound” applies to all acoustic energy with a frequency above humanhearing (20,000 Hertz or 20 kilohertz). Typical diagnostic sonographyscanners operate in the frequency range of 2 to 13 megahertz, hundredsof times greater than this limit. The choice of frequency is a trade-offbetween the image spatial resolution and penetration depth into thepatient, with lower frequencies giving less resolution and greaterimaging depth. Doppler ultrasonography uses the Doppler Effect to assesswhether blood is moving towards or away from a probe, and its relativevelocity. By calculating the frequency shift (up) of a particular samplevolume, for example a jet of blood flow over a heart valve, its speedand direction can be determined and visualized. Ultrasonagraphy andDoppler Ultrasonagraphy can best be understood by S. A. KanaIntroduction to physics in modern medicine, Taylor & Francis, (2003).The basic physics of the Doppler effect involving acoustic andelectromagnetic waves of OCT is similar and many of the signalprocessing techniques (hardware and software) used to estimate theDoppler shift is analogous.

In one embodiment, an ultrasound probe 212 is coupled with the magneticfield generator 100, as shown in FIG. 8. Ultrasound 210 is directed intothe body of the patient by known techniques and the moving red bloodcells backscatter the ultrasonic energy back towards the transducer ofthe ultrasound. The oscillating magnetic field generated by the magneticfield generator 100 increases the contrast of the ultrasonic energy 210received from the red blood cells. The transducer then converts theback-scattered ultrasonic energy 210 into an electrical signal that isprocessed in some known manner to determine an estimate of the flow. Anenhanced ultrasound image is produced, as displayed in FIG. 9.

In one example, a rectal ultrasound probe is coupled with a magnet toevaluate the prostate gland for cancer. Currently, ultrasound is usedfor prostate cancer screening; however, the approach provides poorsensitivity and specificity. Yet, all cancers are known in the art to behighly vascular, so then the application of the magnetic field bygenerator 100 coupled with ultrasound enhances the contrast availablefrom the endogenous RBC's in the prostate for cancer detection at anearlier stage. It is generally known in the art that cancers haveenhanced metabolic properties compared to normal tissues, so thencancerous cells have higher oxygen content from hemoglobin and a greaterconcentration of deoxygenated hemoglobin compared to normal tissues. Anexemplary ultrasound image for prostate cancer screening is shown inFIG. 9.

MM-ODT, OCT, and ultrasound coupled with an oscillating magnetic fieldall can be used in clinical management of patients who needmicrovasculature monitoring, as shown in FIG. 10. The images couldmonitor and determine tissue profusion and viability before, during andafter operation procedures. For example, the images could be used todetect oxygenated and deoxygenated blood supply, detect blood vessellocation, sizes of cancer, vascular tissue abnormality identification,and port-wine stain. Alternatively, the images could monitorphotodynamic therapy or evaluate cranial injuries. While medicalapplications of the embodiments have been described, the embodimentsdisclosed herein are applicable to any circumstance where image contrastis needed for fluids comprising endogenous metallic compositions.MM-ODT, OCT, and ultrasound can be used in various combinations todetect vascular occurrences.

While the invention has been described in connection with variousembodiments, it will be understood that the invention is capable offurther modifications. This application is intended to cover anyvariations, uses or adaptations of the invention following, in general,the principles of the invention, and including such departures from thepresent disclosure as, within the known and customary practice withinthe art to which the invention pertains.

What is claimed is:
 1. A method for imaging a blood flow, comprising:applying an oscillating magnetic field to the blood flow, wherein theblood flow comprises a plurality of hemoglobin molecules and wherein theoscillating magnetic field is greater than 0.14 T at a time during eachoscillatory cycle and oscillating at rate greater than 50 Hz tointeracts with the hemoglobin to cause a change in the blood flow; anddetecting the blood flow by detecting the change in the blood flowcaused by the interaction with the hemoglobin molecules, wherein thechange is detected using an optical coherence tomography system.
 2. Themethod of claim 1, wherein the magnetic movement of hemoglobin moleculesis detected by the equation:${I_{f}a\; 2\sqrt{I_{r}I_{s}{\exp\left\lbrack {{\mathbb{i}}\left( {{2\;\pi\; f_{o}t} + {\frac{4\;\pi\;{z(t)}}{\lambda_{o}}{z(t)}}} \right)} \right\rbrack}}},$where I_(R) and I_(S) are the back scattered intensities from thereference and sample arms, respectively, f_(o) is the fringe carrierfrequency, λ_(o) is the center wavelength of the light source, and z(t)is the RBC displacement.
 3. The method of claim 2, further comprisingoperably coupling the optical coherence tomography system to a probe. 4.The method of claim 3, wherein the detecting the blood flow by detectingthe change in the blood flow caused by the interaction with thehemoglobin molecules, wherein the change is detected using amagnetomotive optical Doppler tomography imaging system.
 5. The methodof claim 4, wherein the magneto-motive optical Doppler tomography systemcomprises the method of providing light energy through aninterferometer; phase modulating the light energy in the interferometerat a modulation frequency; continuously scanning a blood flow samplewith the light energy through the interferometer, wherein the blood flowsample includes a blood flow therein and a structure in which the bloodflow is defined; detecting the magnetic resonance signal reflected offthe moving blood sample and the interference fringes of the light energybackscattered from moving blood sample; and data processing Dopplerfrequency changes of the detected backscattered interference fringeswith respect to said modulation frequency at each pixel of a scannedimage to continuously measure the interference fringe intensities toobtain time dependent power spectra for each pixel location in a datawindow in a continuous scan from which a tomographic image of the bloodflow in and the structure of said scanned blood flow sample is formed.6. The method of claim 5, where phase modulating the light energyincludes aligning a rapid scanning optical delay line, and ceasing phasemodulation when the group phase delay is scanned at 4 kHz.
 7. The methodof claim 6, where detecting the interference fringes of light energybackscattered from the moving blood sample includes reducing the lightsource noise from the interference signal with a dual balancedphotodetector.
 8. The method of claim 7, further including improvingimaging speed with a hardware in-phase and a quadrature demodulator withat least one high-bandpass filter.
 9. The method of claim 8, where thedata processing Doppler frequency changes includes calculating with aKasai autocorrelation velocity estimator.
 10. The method of claim 9,where the continuously scanning of the blood flow comprises threedimensionally scanning the blood flow with a plurality of galvanometers.11. The method of claim 3, wherein the detecting of the change in theblood flow caused by the interaction with the hemoglobin molecules isdetected using a spectral domain phase sensitive optical coherencetomography system.
 12. The method of claim 11, wherein the detecting ofthe change in the blood flow caused by the interaction with thehemoglobin molecules is detected using a swept source phase sensitiveoptical coherence tomography system.
 13. A method for imaging a bloodflow comprising: applying an oscillating magnetic field to the bloodflow, wherein the blood flow comprises hemoglobin molecules, wherein theoscillating magnetic field is sufficient to induce magnetic movement ofhemoglobin molecules having a magnetic susceptibility of about 11×10⁻⁶;and detecting the blood flow with an ultrasound detection system whilethe blood flow is in the presence of the magnetic field.
 14. The methodof claim 13, wherein the applying of the magnetic field comprisestemporally oscillating the magnetic field being greater than or equal to0.14 T at a time during each oscillatory cycle and the magnetic field isoscillating at a rate greater than or equal to 50 Hz to magneticallymove hemoglobin.
 15. The method of claim 14, further comprising couplingthe ultrasound detection system and the magnetic field to a probe. 16.The method of claim 15, wherein the detecting the blood flow bydetecting the change in the blood flow caused by the interaction withthe hemoglobin molecules, wherein the change is detected using amagnetomotive Doppler ultrasound detection system.